Coumarin-3-carboxylic acid salt of an amino alcohol and process of producing the same



Patented Sept. 28, 1937 UNITED STATES PATENT OFFICE COUMARIN 3 CARBOXYLIC ACID SALT OF AN AMINO ALCOHOL AND PROCESS OF PRODUCING THE SALE 1 Otto Dalmer and Fritz von Werder, Darmstadt,

Germany, assignors to Merck & 00., Inc., Rahway, N. 3., a. corporation of New Jersey No Drawing.

Application September 15, 1934,

gig-i323 No. 744,168. In Germany September 22,

11 Claims. (Cl. 260-123) This invention relates to coumarin-carboxylic acid salts of certain aryl-substituted amino alcohols of the type of ephedrine, its homologues and derivatives having thegeneral formula hitherto been known as to the physiological ac tion of coumarin-3-carboxylic acid. It was, therefore, not to be anticipated that the new 3 compounds formed by combining this acid with bases of the group mentioned, would manifest,

instead of a stimulating efiect, a sedative action which is characterized by lethargy and slight narcosls, and which is increased when the com- 35 gounds are administered in relatively large oses.

Furthermore, it is noteworthy that the combination of racemlc trans-ephedrine with coninarin-carboxylic acid is effective in considerably smaller doses than is racemic trans-ephedrine alone. The "therapeutic latitude, that is, the relationship of fatal dose to effective limit, which in racemic trans-ephedrine combined with conmarimcarboxylic acid brings about deepened re- 45 spiration and slight narcosis, and in transephedrine alone brings about slight. irritatlve spasms, is much greater'with the -former and,

therefore, more favorable'with it than with the resulted from pharmacological experiments on mice:

Method 0! application 'f g Fatal dose 5 Racemic tram-ephedrine salt ofcoumart'n-carbozylic acid Malnala- Intravenous 0, 01 0, 06 1o Subcutaneous 0, 025 0, 1 Per 05 0, 025 0, 25

Racemic tram-ephedrine Intravenous 0, 1 0, 176 Subcutaneous. 0, 5 1, 0 Per os l, 0 1, 6 '15 The new compounds are prepared by reacting with coumarin-3-carboxylic acid upon sympathomimetically-acting bases. For example, they may be prepared by mixing the components in soluti n in appropriate solvents and permitting cryst lization, or by melting the components togeth r, or they may be prepared by cross-reaction in solution between salts of coumarin-3- carboxylic acid and salts of ephedrine-like bases.

In the sense of our invention, bases of the ephedrine type are understood to be sympathomimetically effective compounds of its homologues.

and derivatives of the general formula:

1 g I Y H Q as 11- --on I wherein R is a phenyl or substituted phenyl group, and X, Y, and Z are hydrogen or alkyl groups.

The various steps of the process are set forth in the accompanying examples. Obviously, 4 these steps may be modified considerably with respect to their order and number and the speciflc materials used, without departing from'the spirit of the invention substantially as described and claimed, and it is understood that we do not desire to limit ourselves to the specific embodiments shown.

Example I 190 parts by weight of coumarin-3-carboxylic acid are dissolved in 3600 parts by volume of acetone, and 165 parts by weight of racemic transephedrine are dissolved in 1650 parts by volume of acetone. Both solutions are combined while hot and kept boiling on the reflux for half an hour. While boiling, the salt begins to separate and after cooling is filtered off by suction and washed out with cooled acetone. By recrystallization from water, 297 parts by weight of pure salt are obtained in the form of finely formed large crystals, having a melting point of 196.

Example II 825 parts of l-ephedrine and 950 parts of coumarin-3 carboxylic acid are finely pulverized and thoroughly mixed. The mixture is carefully melted in an oil bath at 140. The molten mass after cooling is dissolved in a sinall amount of alcohol; from this solution the salt is precipitated by adding a three-fold volume of ether, and is finally recrystallized from acetone. The product is obtained in the form of colorless needles, which after drying melt at 136-137". 100 parts of water at dissolve 8.29 parts of the salt.

Example III Warm solutions of 21 parts by weight of l-1-phenyl-2-methylamino-ethan-1-ol in 250 parts by volume of acetone are combined with 26.4 parts by weight of coumarin-3-carboxylic acid in 560 parts by volume of acetone. Durin mixing, a crystalline pulp is precipitated. The whole is-boiled for a short time under refluxing. The crystallization product, isolated after cooling, is recrystallized from alcohol and is obtained in the form of fine colorless needles having a melting point of 184.

Example IV 380 parts of coumarin-3-carboxylic acid are dissolved in a large excess of acetone. To the solution, heated to 366 parts of l-adrenaline base are added in small amounts under constant stirring. After all has been added, the stirring is continued for another hour and the temperature slowly increased to Finally the reaction container is closed tightly and left standing for 24 hours at room temperature. Thereafter, the

unchanged l-adrenaline base is filtered oil by suction and washed out with acetone. concentrated filtrate the desired salt is obtained, having a melting point of 162-163.

Example VI 40,000 parts by volume of hot chloroform are poured over 34 parts by weight of l-p-hydroxyphenyl-2-methylamino-ethan-l-ol. After adding From the a solution of 38.8 parts by weight of coumarin-3- oarboxylic acid in 10,000 parts by volume of chlovroform, the whole mixture is heated to boiling for half an hour during refluxing. The diluent is distilled ofi as far as possible, the rest is removed in-vacuo. The residue is recrystallized from a little alcohol. Approximately parts by weight of salt are obtained in the form of solid prisms, having a melting point of 192".

Example VII 1.5 parts by weight of freshly precipitated barium salt of coumarin-3-carboxylic acid are suspended in 70 parts of water without previous drying and shaken with a solution of 2 parts by weight l-ephedrinesulphate for some time, heating the mixture slightly. The change in the outer appearance of the precipitate indicates the.

' RCHOHCH2NHCH3, wherein R is selected from the group consisting of phenyl, aminophenyl, and hydroxyphenyl.

2. The coumarin-B-carboxylic acid salt oi. 1-phydroxyphenyl-2-methyiarnino-ethan-l-ol.

3. The coumarin-3-carboxylic acid salt of racemic trans-ephedrine.

4. The coumarin-3-carboxylic acid salt of i-ephedrine.

5. A process for the production of a coumarin- 3-carboxylic acid salt of a substituted amino alcohol having the general formula R--CHOH- CH:NHCH3, wherein R is selected from the group consisting of phenyl, amino-phenyl, and hydroxyphenyl, which comprises reacting upon said alcohol with coumarin-3-carboxylic acid.

6. A process for the production of the coumarin- 3-carboxylic acid salt' of l-p-hydroxyphenyl-2- methylamino-ethan-1-ol which comprises reacting upon said- 1-p-hydroxyphenyl-2-methyl- -amino-ethan-1-ol with coumarin-3-carboxylic acid. a

'l. A process for the production of the coumarin- 3-carboxylic acid salt of racemic trans-ephedrine which comprises reacting upon racemic transephedrine with coumarin-3-carboxylic acid.

8. A process for the production of the coumarin- 3-carboxylic acid salt of l-ephedrine which comprises reacting upon l-ephedrine with coumarin- 3-carboxylio acid.

9. A process for the production of a coumarin- 3-carboxylic acid salt of a substituted amino alcohol having the general formula RCHOI-I- CH2NHCH3, wherein the radical R is selected from the group consisting of phenyl, aminophenyl, and hydroxyphenyl, which comprises mixing said acid and said alcohol in solution in an inert aliphatic solvent, and thereafter crystallizing out said salt. r

10. A process for the production of a coumarin- 3-carboxylic acid salt of a substituted aminc alcohol having the general formula RCHOH- CH2NHCH3, wherein R is selected from the group consisting of phenyl, amino-phenyl, and hydroxyphenyl, which comprises melting said acid and said alcohol together, cooling the resultant molten mass and dissolving in alcohol, prevgroup consisting of phenyl, amino-phenyl, and

cipitating the salt by the addition of ether, and hydroxyphenyl, which comprises cross reaction in thereafter crystallizing said salt from acetone. solution between a salt of coumarin-3-carboxylic 11. A process for the production of a. coumarinacid a and salt of a substituted amino alcohol.

5 3-carboxylic acid salt of a. substituted amino alcohol having the genera formula RCHOH- O'I'I'O DALMER. CH2NHCH3, wherein R is selected from the FRITZ VON WERDER. 

